Methamphetamine, Behaviorand Brain Imaging

Edythe D. London, Ph.D.David Geffen School of Medicine, UCLA

AMPHETAMINESIncluding Methamphetamine

• MOST COMMONLY USED ILLICIT DRUG AFTER CANNABIS

• >35 million regular users (WHO, 1997)

• 9.4 million Americans have used (DEA, 1999)

•No longer restricted to the Southwest

• Use steeply increased and expanded geographically

What do we know about methamphetamine?

•Meth, crystal, speed•CNS stimulant

•Injected, smoked, snorted, ingested orally

• Amphetamine derivative (prescribed 1950s, 1960s for

obesity, depression)• Prolonged , high level use

produces dependence.

What are the effects of methamphetamine?

• Cardiac arrhythmias• Stomach cramps

Effects on the brain:• stroke

• shaking• anxiety

• insomnia• paranoia

• hallucinations

What are the goals of brain imaging?

Figure out how drugs act.

Characterize addiction.

What’s wrong in the brain? What circuits?

Advance treatment.Provide a rational basis to design medicines or

cognitive-behavioral therapies.

Methamphetamine users have emotional and cognitive deficits.

.Where is the problem in the brain?

Focus on cortical-limbic circuits.

The orbitofrontal and cingulate cortices participate in emotional experiences and

cognitive processing.

R.J. Dolan, 2002

The anterior cingulate and insular cortices participate in emotional experiences.

The amygdala links perception with emotion and memory.

Affective State Varies Over Time

Drug-Taking

Dependence

Cessationof Drug Use

craving, negative affectco-morbid psychiatric

conditions

Relapse

Withdrawal

Positiv

e Affe

ct

Methamphetamine users have Methamphetamine users have cognitive deficits in early abstinence.cognitive deficits in early abstinence.

•working memory

•learning

•abstract thinking

• logic

113 (3.4) **124 (3.4) Words Remembered

19.5 (1.8) *24.0 (1.3)Discrimination Learning (# correct)

20.5 (3.0)

Controls (n = 23)

35.3 (3.8) **

MA (n = 21)

Learning Selective Reminding

Reminders (#)

Cognitive DeficitsCognitive Deficits

significant from control, *p<.05; **p <.01

63.1 (2.2) 54 (2.3) **Digit symbol (# correct)Working Memory

HypothesesHypotheses

Methamphetamine abusers in early abstinencehave affective deficits as well.

These deficits reflect dysfunction in specific brain regions.

Depression Scores in Abstinent Depression Scores in Abstinent Methamphetamine UsersMethamphetamine Users

0

2

4

6

8

10

12

1 2 3 4 5

Weeks of MA AbstinenceWeeks of MA Abstinence

BD

I Sco

re

control control

Methamphetamine craving drops Methamphetamine craving drops dramatically over 3 weeks.dramatically over 3 weeks.

0

0.5

1

1.5

2

2.5

3

3.5

4

4.5

5

1 2 3 4 5

Weeks of MA Abstinence

VA

S S

core

• MA and control groups

• Urine drug screens to show MA use

• Abstinence maintained on a research ward

• PET scan and cognitive tests

• PET scan -- FDG/auditory CPT

MethodsMethods

Fluorodeoxyglucose (FDG) is injected as a tracer for brain function.

                                                                                                                                                                                                       

                             

[18F]-labeled 2-deoxyglucose (FDG) is used in neurology, cardiology and oncology to study glucose metabolism. In cardiology, [18F]-labeled FDG can be used to measure regional myocardial glucose metabolism. Although glucose is not the primary metabolic fuel of the myocardium, glucose utilization has been extensively studied as a metabolic marker in both diseased and normal myocardium. Because [18F]-labeled FDG measures glucose metabolism it is also useful for tumor localization and quantitation. FDG is potentially useful in differentiating benign from malignant forms of stimulated osteoblastic activity because of the high metabolic activity of many types of aggressive tumors.

[ Tracers TOC | Back to Doses ] Copyright © 1998 Crump Institute for Biogical Imaging. Web Curator

FDG is taken up by brain regionsin proportion to their activity.

It is visualized in the brain by PET scans.

PET Scanning A Nuclear Medicine procedure

Detectors linked to a computer system reconstruct an image.

PET scans with FDG show normal whole brain metabolism in early

abstinence from methamphetamine.

0

2

4

6

8

10

12

CM

Rg

lc (

mg

/10

0g

/min

)C

MR

glc

(m

g/1

00

g/m

in)

Control Control MAMA

Brain activity varies with age in methamphetamine users –

not in control subjects.

789

1011121314

20 30 40 50AGE (years)

Metabolic rate(mg/100 g/min)

MA reduces reserve – less compensation for aging.

Sig

nal In

ten

sit

y

Sig

nal In

ten

sit

y

(Wh

ite M

att

er)

(Wh

ite M

att

er)

Age (years)Age (years)

1010

55

00

-- 55

-- 1010

--1515

-- 20202020 3030 4040 5050

White matter (MRI scans) varies with White matter (MRI scans) varies with age in methamphetamine users. age in methamphetamine users.

Cortical white matter increases until the mid-30s in healthy people – not in methamphetamine users.

Regional brain activity is abnormal in methamphetamine abusers

during early abstinence.Anterior Cingulate

PosteriorCingulate

VentralStriatum/

2.5

1.5

1

2

3

3.5

0.5

Control> MA

t-values

MA >Control

5

3

1

2

4

Amygdala

Orbitofrontal Dysfunction in Methamphetamine Abusers

t-values

2.5

1.5

1

2

3

3.5

0.5

Control> MA

MA >Control

5

3

1

2

4

Depressive Symptoms in MA AbusersPositive Covariance with Activity

of Anterior Cingulate and Amygdala

5

3

1

2

4

67

t-values

ACCAmygdala

Anxiety in MA Abusers Negative Covariance with Cortical ActivityPositive Covariance with Amygdala Activity

Amygdala5

3

2

4

6

7

1

t-values

5

3

1

2

4

Negative Positive Covariance

Loss of Cortical Inhibition of the Amygdala

2.5

1.5

1

2

33.5

0.5

Control> MA

t-values

MA >Control

5

3

1

2

4

Cues exaggerated responses

anxiety, craving

ACC

AmygdalaOFC

Infralimbic Cortex Role in Recall of Extinction

Infralimbic neurons signal extinction memory

Habit. + Cond. Extinction Extinction

Habit. Cond. Extinction Extinction

Day 1 Day 2

Seconds after tone onset

% F

ree

zin

g t

o

ton

e

Sham

vmPFC

Lesion

20

10

0

20

10

0

20

10

021-1 0 -1-1 0 01 12 2

vmPFC lesions block recall of extinction Day 1 Day 2

80

60

40

20

0S

pik

es

IL

IL

Adapted from GJ Quirk and DR Gehlert, 2003

Orbitofrontal dysfunction shows recovery with continued

abstinence.t-values

2.5

1.5

1

2

3

3.5

0.5

Control> MA

MA >Control

5

3

1

2

4

Some cognitive functions improve with continued abstinence.

36

38

40

42

44

46

48

50

52C

orre

ct r

espo

nses

/45

sec

Controls

METH, 1-7 days abstinent

METH, 3 mo abstinent

N = 22

*

Conclusions

Cortical dysfunction in methamphetamine dependence

involves regions associated with negative affect:

Orbitofrontal, Cingulate, Insular

Negative affect (depression, anxiety)-- Has direct effects on drug taking

-- Has indirect effects through influencing executive cognitive functions.

Can imaging help to develop effective treatments?

Treatment and Sobriety

Drug Use Behavior

Responsible Behavioral

Choice

Knowledge of affected circuitry can• Identify targets for medications.

• Identify brain systems amenable to behavioral therapy- a moving target.

Walter Ling Richard Rawson

Sara Simon Steven Berman

Roger Woods Mark Mandelkern

John Matochik Bradley Voytek

Aaron Lichtman Varughese Kurian

Ann Shinn Jennifer Bramen

Jennifer Learn

Collaborating InvestigatorsCollaborating Investigators